tbuckley/cabot-search huggingface dataset:
Assessing tumor-infiltrating immune cells and outcomes with cisplatin- versus carboplatin-based treatment in advanced urothelial cancer (UC): Survival analysis of three platinum-treated UC cohorts.
Authors: Konrad Stawiski, Júlia Perera-Bel, Alejo Rodriguez-Vida, Núria Juanpere Rodero, Kent William Mouw, Aristotelis Bamias, Filipe Lf Carvalho, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2023)

4583 Background: The association between tumor-infiltrating immune cells and the response to platinum-based chemotherapy (cisplatin vs carboplatin) in advanced urothelial cancer is not well characterized. We dissected the immune microenvironment of 3 large UC cohorts to define populations of immune cells associated with survival following carboplatin- or cisplatin-based chemotherapy. Methods: Two advanced UC cohorts – Hospital del Mar (HM; n = 55) and GREEK (n = 62) – treated with platinum-based chemotherapy were profiled using bulk RNA sequencing (RNA-seq) with tumor-infiltrating immune cells inferred using CIBERSORTx. Our findings were validated in a publicly available platinum-treated UC cohort (n = 93; Taber et al. Nat Comm 2020). Additionally, we assessed the impact of tumor-infiltrating immune cells in IMvigor210, an anti-PD-L1 treated cohort. Analysis was adjusted by tumor stage, and treatment regimen (cisplatin, carboplatin, atezolizumab) to determine associations between tumor-immune cell populations and overall survival (OS). Results: In platinum-treated patients, increased lymphoid cell infiltration was associated with improved OS. Specifically, the presence of naive and memory B-cells and CD4+ T cells was associated with prolonged OS (Table). Interestingly, infiltration of memory B-cells was associated with a better prognosis in patients treated with cisplatin (HR = 0.14) and detrimental in patients treated with carboplatin (HR = 249.53; difference p = 0.006). Additionally, macrophages (HR = 3.44; p = 0.027) and resting dendritic cell (HR = 41.47; p = 0.009) infiltration was associated with worse OS in patients treated with platinum therapy alone, but enrichment of pro-inflammatory M1 macrophages was associated with prolonged OS in patients treated with immunotherapy (p &lt; 0.001). Conclusions: Immune cell infiltration is associated with differential outcomes to cisplatin- and carboplatin-based chemotherapy in advanced UC. Our findings suggest better OS in advanced UC treated with cisplatin in tumors enriched with memory B-cells compared to carboplatin treatment. [Table: see text]
Relations between mutant <i>KRAS</i> and <i>TP53</i> subtypes and other co-mutations in pancreatic cancer.
Authors: Soniya Abraham, Janie Yue Zhang, Zenta Walther, Jay Parekh, Jill Lacy, Michael Cecchini, Yiduo Hu
Journal: Journal of Clinical Oncology (2023)

e16294 Background: The most common mutations in pancreatic cancer are found in the KRAS, TP53, CDKN2A, or SMAD4 genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood. Methods: We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of KRAS and TP53, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests. Results: One hundred fifty-nine patients were identified and KRAS mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%). TP53 mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%). TP53 LOF mutations were more common in tumors with KRAS WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely, TP53 GOF mutations were more common in tumors with G12R (26.3%) and other KRAS mutations (23.1%), than in KRAS WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between KRAS subtypes (p=0.48) or TP53 subtypes (p=0.52). Patients with TP53 WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with TP53 mutations, p=0.20). When each KRAS subtype was examined, patients with tumors with G12V but no TP53 mutation had longer OS (median 2.42 years) than those with WT KRAS or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the KRAS WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others. Conclusions: In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that KRAS or TP53 mutation subtypes had no significant impact on OS. Different KRAS subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.[Table: see text]
Phenotypic differences related to homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) treated in routine care settings in the United States (US).
Authors: Arthur Sillah, Gboyega Adeboyeje, Liam Lee, Mike Gart, William M. Saunders, Brandon Wang, Poras Dave, Sandy English, Simon Blanc
Journal: Journal of Clinical Oncology (2023)

e17047 Background: Recent evidence suggests mutations in HRR genes predict clinical benefit from treatment with PARP inhibitors in patients (pts) with mCRPC. Little is known about the prevalence, clinical and prognostic phenotypes associated with HRR-mutated (HRRm) mCRPC pts receiving routine oncology care in the US. We assessed HRRm positivity rate and described difference in phenotypic factors between HRRm+ and HRRm- mCRPC patients receiving routine care in community oncology settings. Methods: In this retrospective cohort study, we identified biologically male pts with mCRPC, ≥18 years, who received HRRm testing and on systemic anti-cancer treatment from 5/1, 2020 – 3/31, 2022, from the Integra Connect database, an electronic medical record (EMR) and claims database of US cancer pts in community oncology. We defined 2 cohorts based on their HRRm status (defined by the presence of an alteration in at least 1 of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). We described age and race (at diagnosis), cancer stage and Gleason score (at staging), and line of therapy (LOT), Eastern Cooperative Oncology Group (ECOG) performance status, prostate-specific antigen (PSA) values and microsatellite instability (MSI) status using values closest to mCRPC diagnosis. HRR tests were stratified by germline, ctDNA, and solid tumor. Results: The study cohort comprised 376 HRRm-tested pts: by ctDNA only – 29%, germline only – 16.2%, solid tissue only – 18.4% and &gt; 2 testing types – 33.5%. 96 had HRRm+ mCRPC (25.5%). Median (IQR) age at diagnosis for both cohorts was 67 (43-89) years and there were no statistically significant differences in age, race, stage, Gleason score, PSA value, LOT or ECOG by HRRm status. HRRm+ rates by ctDNA, germline, and solid tissue testing were 26.6%, 13.1% and 21.7%, respectively. Of the 126 patients with &gt; 2 testing types, HRRm+ rate was 30.9%. A higher, but not statistically significant, proportion of HRRm+ pts had Gleason scores 9-10 compared to HRRm- pts (54.8% vs 48.6%). Of HRRm- pts, 10.2% had MSI-H status compared to 6.5% in HRRm+ pts. Conclusions: In this real-world cohort of HRR gene-tested pts with mCRPC, we observed a 25.5% HRRm+ rate, which suggests the prevalence for HRR mutation is significant enough to warrant testing for all pts with mCRPC. Further research is needed to examine the impact of these findings on overall survival and other clinical outcomes.
Matching-adjusted indirect treatment comparisons (MAIC) of sotorasib vs trifluridine/tipiracil (T/T) and regorafenib as monotherapy in chemorefractory <i>KRAS </i>G12C-mutated metastatic colorectal cancer (mCRC).
Authors: Timothy Jay Price, Scott Kopetz, Yasutoshi Kuboki, Hans Prenen, Istvan Matyas Majer, Marko Rehn, Emily Chan, Marwan Fakih
Journal: Journal of Clinical Oncology (2023)

3560 Background: In the single-arm phase 1/2 CodeBreaK 100 study (NCT03600883) evaluating sotorasib monotherapy in KRAS G12C-mutated mCRC patients whose disease progressed on or after fluoropyrimidine, oxaliplatin, and irinotecan treatment, the overall response rate was 12%, and the median progression-free survival (PFS) and overall survival (OS) was 4.2 and 13.4 months, respectively (data cutoff March 2021, n = 91). To compare the efficacy and safety of sotorasib with standard of care (SOC) T/T and regorafenib as monotherapy treatments, MAICs were performed. Methods: Clinical outcomes and adverse events (AEs) were compared from representative studies in mCRC patients who received sotorasib 960 mg once daily in CodeBreaK 100, T/T in the phase 3 RECOURSE study (NCT01607957, n = 534), and regorafenib in the phase 3 CORRECT study (NCT01103323, n = 505). By weighting individual patient-level data from CodeBreak 100, differences in available baseline characteristics considered to be prognostic factors, including age, race, sex, type of cancer (colon vs. rectum), ECOG performance status, time from diagnosis of metastatic disease, number of metastatic sites, number of prior lines of therapy, and prior bevacizumab treatment, were adjusted with the MAIC. MAICs compared sotorasib with T/T and regorafenib separately. Odds ratios (ORs) were estimated for objective response rates, hazard ratios (HRs) were used for PFS and OS. AEs were compared descriptively. Results: The effective sample size of sotorasib with matched characteristics consisted of 29 and 56 patients in the T/T and regorafenib comparison, respectively. The MAIC results showed that treatment with sotorasib increases the likelihood of response to treatment, with an adjusted OR of 8.5 vs T/T and 16.1 vs regorafenib. Sotorasib decreased the risk of progression or death by 41% vs T/T and 45% vs regorafenib (Table). Grade 3+ treatment-emergent AEs occurred in 37%, 69%, and 78% of sotorasib-, T/T-, and regorafenib-treated patients, respectively. Conclusions: The analyses suggest that sotorasib monotherapy is associated with a statistically significant and clinically meaningful improvement in response rates, PFS and OS vs. T/T and regorafenib in heavily pretreated chemorefractory KRAS G12C-mutated mCRC patients. The analyses are limited by the decreased sample size for sotorasib, the lack of KRAS G12C-specific data in SOC studies, and the impact of differences in post-progression treatments on OS across studies. [Table: see text]
Molecular and cytogenetics abnormalities in acute myeloid leukemia at Puerto Rico.
Authors: William Doel Marrero-León, Hector R. Cintron-Colon, Steven Cruz-Rodriguez, William Caceres, Cristian I. Rodriguez-Arocho, Alexis Cruz
Journal: Journal of Clinical Oncology (2023)

e19005 Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease. Specific cytogenetic and molecular features permit stratification of this disease. Prognosis within these categories varies widely. Determining optimal management has been complicated by the multiple molecular disease subsets with different responses to standard therapeutics. The comprehensive genetic analysis of AML in the past 10 years has revealed recurrent, somatically mutated genes, leading to the development of new targeted therapies including inhibitors of FLT3 and IDH. Decisions about the choice of therapy in patients with AML currently depend on the identification of a selected set of genetic markers at diagnosis. At Puerto Rico, AML data of cytogenetic and molecular markers is lacking. According to the Puerto Rico Cancer Registry from 2015 to 2019 a total of 551 cases of AML were reported. The San Juan City Hospital-hematology oncology department is one of the major referral centers on the island for initial evaluation and management of AML. The objective of our retrospective study was to identify the most common cytogenetic and molecular abnormalities present in our population. Patient conditions were stratified as favorable, intermediate, or high risk, in terms of prognosis using the ELN revised 2022 stratification. Methods: This study examined the frequency of molecular markers in newly diagnosed (ND) patients with AML. We evaluated patients that were at least 18 years of age or older with cytogenetic and molecular analysis in a period of 4 years (2019-2022). All data regarding demographic, bone marrow biopsy, cytogenetics, and molecular markers were obtained from electronic medical record at our institution with institutional review board approval. Results: A total of 140 patients with ND AML were identified during the study period. 58% female and 42% male with a median age of 57 years old at time of diagnosis. In terms of molecular markers, the most common were RUNX1 (22%), follow by IDH2 (14%), FLT3-ITD (14%) and TP53 (11%). Complex cytogenetics was identified in 40% patients, and 34% had Myelodysplasia related cytogenetic. Using the ELN 2022 criteria to classify AML patients in terms of risk with cytogenetics and molecular markers, our study revealed 21% favorable risk, 31% intermediate, and 48% adverse. Conclusions: Our study suggests that our population has higher prevalence of AML with myelodysplasia-related gene mutations and molecular related to adverse risks, such as RUNX1. Further studies with appropriate sub-group analysis need to be followed to determine if there is any genetical predisposition on the puertorrican population for myelodysplasia related genes or for RUNX1.
Molecular profiling as a predictor of treatment response and survival in unresectable pancreatic ductal adenocarcinoma.
Authors: Rodrigo Paredes, Marcela Banegas, Santiago Sucre, Cristina Ponce, Ahmed Anwer Ali Rattani, Mary Linton Bounetheau Peters
Journal: Journal of Clinical Oncology (2023)

e16279 Background: To date, few targetable mutations have been found to enhance PDAC treatment. Next-generation sequencing (NGS) of somatic mutation profiles may help tailor cytotoxic chemotherapy selection and guide translational research. Methods: We analyzed NGS data from a retrospective cohort of 142 patients with unresectable biopsy-proven PDAC from August 2009 to December 2022. Individual mutations were grouped into 14 distinct signaling pathways: cell cycle, DNA damage repair, KIT, ErbB2, TP53, MAPK-RAS, PIK3, TGF-beta, NOTCH, ALK, FLT3, FGFR, and WNT. Treatment selection, duration of response, and survival were recorded. We stratified patients based on their first-line therapy, either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (GA). We present median time-to-first progression (PFS1) and overall survival (OS) based on the presence or absence of mutations in these pathways. The time-to-event endpoint was estimated by the Kaplan-Meier method. Results: Of 142 samples, 131 were analyzed for PFS1; 57 received FFX, and 60 received GA. In the FFX group, no pathway predicted PFS1 with statistical significance. In the GA group, KIT pathway mutations (n = 10) showed improved PFS1 vs. non-KIT mutated tumors (10.3 mos vs. 6.2 mos, p = 0.02). Similar improvement in PFS1 was seen for mutations in the PIK3 pathway (n = 25, 6.6 vs. 5.7, p = 0.02) and FLT3 pathway (n = 4, 13.1 vs. 6.2, p = 0.02). 125 samples were analyzed for OS. KIT pathway mutations (n = 21) showed a better OS vs. non-KIT mutated samples (21.3 mos vs. 12.2 mos, p = 0.04), as did NOTCH mutated samples (n = 44, 15 vs. 12.3, p &lt; 0.01). FLT3 pathway mutations showed a trend toward improved OS (23.6 vs. 13, p = 0.3). PIK3 mutated tumors had no difference in OS. 8 samples were KRAS WT; removing these from the analysis did not change the results. Conclusions: In this sample, KIT, FLT3, and PIK3 pathway mutated tumors had improved PFS1 with GA (but not FFX) treatment. Tumors with KIT and NOTCH pathway mutations had an improved OS. This and similar analyses could help identify potential drivers of treatment response for unresectable pancreatic tumors. [Table: see text]
Geographical and baseline clinical characteristics of participants enrolled in hepatocellular carcinoma (HCC) trials: Analysis of US FDA approvals.
Authors: M. Naomi Horiba, Shruti U. Gandhy, Sandra J. Casak, Steven Lemery, Paul Kluetz, Richard Pazdur, Lola A. Fashoyin-Aje
Journal: Journal of Clinical Oncology (2023)

4115 Background: Globalization of drug development is increasing, with reliance on data from patients accrued to large, randomized studies across continents. In addition to appropriate racial/ethnic representation, trials submitted to support FDA approvals should reflect the etiology and treatment patterns of HCC in the US. We conducted a pooled analysis of patient-level data from the HCC trials supporting approved marketing applications in the US to characterize geographical and baseline variables in clinical trials. Methods: Datasets from applications which received FDA approval for HCC between 2010-2022 were identified. The following data was abstracted: country, baseline disease characteristics (median age, HCC etiology, extent of tumor, and Child-Pugh score), and prior treatments received. Geographical region was recoded using categories observed by the United Nations M49 standard, based on country of enrollment reported in the datasets. Results: Variables that were defined differently across studies included region of enrollment, some categories of etiology, and prior therapy. Overall, the rate of HBV etiology was higher than that observed among patients with HCC in the US (20%), while the rate of HCV etiology was lower than in the US (50%). Conclusions: Variability in patient populations exist across trials submitted to FDA based on the regions that were targeted for enrollment and eligibility criteria. Global trials may be appropriate to support drug approvals for HCC; however, to ensure results are applicable to US patients, sponsors should select sites that represent a similar population with respect to racial/ethnic representation, disease etiology, and treatment patterns. [Table: see text]
Molecular profiling and characterization of the tumor immune microenvironment (TME) in appendiceal carcinoma (AC).
Authors: Muneeb Rehman, Yasmine Baca, Joanne Xiu, Phillip Walker, Emil Lou, Wafik S. El-Deiry, Heinz-Josef Lenz, Anthony F. Shields, John Marshall, Curtis Johnston, Matthew James Oberley, Sanjay Goel, Benjamin Adam Weinberg, Andreana Natalie Holowatyj
Journal: Journal of Clinical Oncology (2023)

3622 Background: The rarity of AC presents challenges in understanding disease pathogenesis. We previously showed that AC has higher rates of mutations in KRAS and GNAS and lower rates of TP53, APC, and PIK3CA than CRC. The appendix also has many lymphoid clusters and regulates IgA production in the large bowel, suggesting that AC may be subject to more lymphocytic regulation than CRC. We sought to characterize the molecular profile and TME across AC histopathological types. Methods: AC samples were analyzed by DNA sequencing (592 genes, NextSeq, or whole exome sequencing, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) for molecular profiling, including microsatellite instability (MSI), mismatch repair (MMR), PD-L1 (SP142), and tumor mutational burden (TMB). Microenvironment Cell Population-counter Quantiseq was used to quantify tumor immune contexture using WTS. AC histopathology was derived from pathology reports. Mann-Whitney U and ChiSquare tests were applied as appropriate, with P-values adjusted for multiple comparisons using Benjamini-Hochberg. Results: AC (N = 731) were grouped by histology: 5% goblet cell (GC), 6% high-grade adenocarcinoma (HGA), 14% low grade mucinous (LGM), 33% mucinous adenocarcinoma (MA), 1% pseudomyxoma peritonei (PMP), 6% signet ring cell carcinoma (SRC), and 35% adenocarcinoma not otherwise specified (NOS) (see Table). Age at collection and PD-L1+ (0-5.2%) did not differ by histopathology. Seven patients had dMMR (4 NOS and 3 MA). Median TMB was significantly higher in NOS vs. GC (4 mutations/megabase vs 2, q &lt; 0.001), NOS vs. LGM (4 vs 3, q = 0.048), MA vs. GC (4 vs 2, q &lt; 0.001), and MA vs. LGM (4 vs 3, q = 0.037). Distinct TME patterns were observed in NOS vs. MA (median cell fraction: dendritic cells 0.07 vs 0, q &lt; 0.01; M2 macrophages 0.055 vs 0.042, q = 0.030; natural killer cells 0.034 vs 0.031, q = 0.011; CD4 T cells 0.006 vs 0, q = 0.044) and GC vs. MA (M1 macrophages 0.039 vs 0.057, q = 0.021; dendritic cells 0.012 vs 0, q &lt; 0.01; B cells 0.061 vs 0.050, q = 0.013; M2 macrophages 0.074 vs 0.042, q &lt; 0.01; natural killer cells 0.041 vs 0.031, q = 0.01; and neutrophils 0.017 vs 0.038 q = 0.045). T cell inflamed signature (TIS) and immune-oncology (IO) marker gene expression were higher in HGA and lower in LGM and MA. Somatic mutation rates differed by histopathology (see Table). Conclusions: There is significant heterogeneity in TMB, TME, and mutational profiles across AC histologies. MA has a particularly immune-cold TME shown by lower infiltration of lymphocytes, TIS, and IO gene expression. These findings are critical to identify novel biomarkers and develop new therapeutic strategies for AC. [Table: see text]